1-phenyl-3-dimethylaminopropane compounds with a pharmacological effects

ABSTRACT

1-phenyl-3-dimethylaminopropane compounds corresponding to the formula I 
                 
 
a method of preparing them, and the use of these substances as analgesic active ingredients in pharmaceutical compositions.

CROSS REFERENCE TO RELATED APPLICATION

This application is a reissue of U.S. Pat. No. 6,248,737.

BACKGROUND OF THE INVENTION

The present invention relates to 1-phenyl-3-dimethylaminopropanecompounds, to a method of preparing them, and to the use of thesesubstances as pharmaceutical active ingredients.

The treatment of chronic and non-chronic pain situations is of greatimportance in medicine. This is reflected in the large number ofpublications. Thus, for example, 1-naphthyl-3-aminopropane-1-ols with ananalgesic-narcotic effect are known from EP 176 049. Secondary andtertiary alcohols with γ-amino groups are described in J. Pharm. Sci.59, 1038 (1970) and in J. Prakt. Chem. 323, 793 (1981);phenyl-dimethylaminopropanols containing a para-substituted phenylradical are described in Chem. Abstr. 54, 20963c (1960) and in Chem.Abstr. 63, 6912e (1965). These compounds also possess analgesicproperties. In contrast, the 3-dimethylaminopropan-1-ols containing2-phenyl radicals described in DE 32 42 922 have an antidepressanteffect. The 1-phenyl-propan-1-ols described in J. Pharm. Sci. 57, 1487(1968) have different pharmacological effects depending on the γ-azaring.

Opioids have been used for many years as analgesics for the treatment ofpain, although they give rise to a series of side effects, for exampleaddiction and dependency, respiratory depression, gastrointestinalinhibition and obstipation. They can therefore only be given over anextended period of time or in higher doses subject to specialprecautionary measures such as special prescription regulations(Goodman, Gilman in “The Pharmacological Basis of Therapeutics”,Pergamon Press, New York (1990)).

Tramadolhydrochloride—(1RS,2RS)-2-[(dimethylamino)methyl]-1-(3-methoxyphenyl)cyclohexanol hydrochloride—assumes a special position amongstcentrally-acting analgesics, since this active ingredient gives rise toa pronounced inhibition of pain without the side effects which are knownfor opioids (J. Pharmacol. Exptl. Ther.4 267, 331 (1993)). Tramadol is aracemate and consists of identical amounts of (+) and (−) enantiomer. Invivo the active ingredient forms the metabolite O-desmethyl-tramadol,which is likewise present as a mixture of enantiomers. Investigationshave shown that both the enantiomers of tramadol and the enantiomers oftramadol metabolites contribute to the analgesic effect (J. Pharmacol.Exp. Ther. 260, 275 (1992)).

SUMMARY OF THE INVENTION

The underlying object of the present invention was to provide substanceswith an analgesic effect, which are suitable for the treatment of severepain without giving rise to the side effects which are typical ofopioids.

A further object was to provide analgesic substances which do notexhibit the side effects, for example nausea and vomiting, which occurduring treatment with tramadol in some cases.

It has been found that these stringent requirements are fulfilled bycertain 1-phenyl-3-dimethylaminopropane compounds. These substances arecharacterized by a pronounced analgesic effect which is significantlyenhanced compared with that of tramadol.

The present invention accordingly relates to1-phenyl-3-dimethylaminopropane compounds of formula I

in which

-   X represents OH, F, Cl, H or an OCOR⁶ group in which R⁶ is a    C₁₋₃-alkyl group;-   R¹ is a C₁₋₄-alkyl group;-   R² represents H or a C₁₋₄-alkyl group and R³ represents H or a    straight chain C₁₋₄-alkyl group, or R² and R³ together constitute a    C₄₋₇ cycloalkyl radical, and-   if R⁵ is H, R⁴ represents meta-O-Z, where Z is H, C₁₋₄-alkyl,    PO(OC₁₋₄-alkyl)₂, CO(OC₁₋₅-alkyl), CONH—C₆H₄—(C₁₋₃-alkyl) or    CO—C₆H₄—R⁷, wherein R⁷ is ortho-OCOC₁₋₃-alkyl or meta- or    para-CH₂N(R⁸)₂, where R⁸ is C₁₋₄-alkyl or 4-morpholino, or R⁴.    represents meta-S-C₁₋₃-alkyl, meta-Cl, meta-F or meta-CR⁹R¹⁰R¹¹,    ortho-OH, ortho-O-C₂₋₃-alkyl, para-F or para-CR⁹R¹⁰R¹¹, where R⁹,    R¹⁰ and R¹¹ represent H or F, or-   if R⁵ represents Cl, F, OH or O—C₁₋₃-alkyl in the para-position, R⁴    represents Cl, F, OH or O—C₁₋₃-alkyl in the meta-position, or-   R⁴ and R⁵ together represent 3,4-OCH═CH— or 3,4-OCH═CHO—, as    diastereoisomers or enantiomers in the form of free bases or salts    of physiologically acceptable acids.

1-phenyl-3-dimethylaminopropane compounds of formula I are preferred inwhich X constitutes OH, F, Cl or H; R¹ represents a C₁₋₄-alkyl group; R²represents H or CH₃, and R³ represents H or CH₃, and if R⁵ is H, R⁴represents OC₁₋₃-alkyl, —OH, —S—C₁₋₃-alkyl, F, Cl, CH₃, —CF₂H or —CF₃ inthe meta-position, or para-CF₃, or if R5 is a para-Cl or para-F, R⁴represents meta-Cl or meta-F, or R⁴ and R⁵ together represent3,4-OCH═CH—.

1-phenyl-3-dimethylaminopropane compounds of formula I are particularlypreferred in which the R² and R³ radicals have different meanings, inthe form of their diastereoisomers of configuration Ia

The present invention also relates to a method of preparing1-phenyl-3-dimethylaminopropane compounds of formula I, in which thevariable X represents OH, which is characterized in that aβ-dimethylaminoketone of formula II

is reacted with an organometallic compound of formula III

in which Z represents MgCl, MgBr, MgI or Li, to form a compound offormula I in which X represents OH.

The reaction of a β-dimethylaminoketone with a Grignard reagent offormula III, in which Z represents MgCl, MgBr or MgI, or with anorganolithium compound of formula III, can be carried out in an aliphatic ether, for example diethyl ether and/or tetrahydrofuran, attemperatures between −70° C. and +60° C. Organolithium compounds offormula II can be obtained by the replacement of halogen by lithium, forexample, by reacting a compound of formula III, in which Z representsCl, Br or I, with a solution of n-butyllithium in n-hexane.β-dimethylaminoketones of formula II can be obtained from ketones ofgeneral formula IV

by reaction with dimethylamine hydrochloride and formaldehyde in glacialacetic acid or in a C₁₋₄-alkyl alcohol or by reaction withdimethylammonium ethylene chloride in acetonitrile using acetyl chlorideas a catalyst (Synthesis 1973, 703).

Upon reaction of a β-dimethylaminoketone of formula II, in which thevariables R² and R³ have different meanings, with an organometalliccompound of formula III, 1-phenyl-3-dimethylaminopropane compounds offormula I are obtained having the relative configuration of formula Ia

in which the X and the dimethylamino group are disposed threo inrelation to each other. In contrast, if the reaction for the preparationof 1-phenyl-1-hydroxy-3-aminopropanes were carried out according to themethod disclosed in DD 124 521, i.e. if β-aminoketones corresponding tothe formula

were reacted with an alkyl Grignard reagent R¹MgHal, this would resultin compounds with the relative configuration Ib

in which the OH X group and the dimethylamino radical are disposederythro in relation to each other.

1-phenyl-3-dimethylaminopropane compounds of formula I, in which R⁴and/or R⁵ constitute the OH group, can be prepared from thecorresponding 1-(4(5)-methoxyphenyl)-3-dimethylaminopropanol compoundsby selective ether cleavage with diisobutylaluminium hydride in anaromatic hydrocarbon, for example toluene, at a temperature between 60and 130° C. (Synthesis 1975, 617).

The present invention also relates to a method of preparing1-phenyl-3-dimethylaminopropane compounds of formula I, in which Xrepresents H, which is characterized in that a compound of formula I, inwhich X represents Cl, is reacted with zinc borohydride, zinccyanoborohydride and/or tin cyanoborohydride.

The reaction is usually conducted in a solvent, for example diethylether and/or tetrahydrofuran, at a temperature between 0° C. and 30° C.

Compounds of formula I, in which X is H and R⁴ and/or R⁵ constitute theOH group, can be prepared from the corresponding methoxyphenyl compoundsby heating them for several hours with concentrated hydrobromic acid(Chem. Rev. 54, 615 (1954); J. Am. Chem. Soc. 74, 1316 (1952)).

The present invention further relates to a method of preparing1-phenyl-3-dimethylaminopropane compounds of formula I, where Xrepresents F, which is characterized in that a compound of formula I, inwhich X represents OH, is reacted with dimethylaminosulfur trifluoridein a solvent.

Suitable solvents include dichloromethane, 1,1,2-trichloroethane and/ortoluene. The reaction is usually conducted at a temperature between −50°C. and +30° C. (Org. React. 35, 513 (1988)). If a compound of formula Iwith X═OH is used in which R⁴ and/or R⁵ constitute OH groups, these OHgroups must be protected before reaction with the fluorine compound, forexample by reaction with benzoyl chloride.

The present invention also relates to a method of preparing1-phenyl-3-dimethylaminopropane compounds of formula I, in which Xrepresents Cl, which is characterized in that a compound of formula I,in which X represents OH, is reacted with thionyl chloride.

The reaction is usually conducted in the absence of solvent at atemperature between 0° C. and 20° C. Replacement of OH by Cl is effectedwhile maintaining the configuration.

The present invention also relates to a method of preparing1-phenyl-3-dimethylaminopropane compounds of formula I, in which Xrepresents an OCOR⁶ group where R⁶ is a C₁₋₃-alkyl, which ischaracterized in that a compound of formula I, in which X represents OH,is reacted with an acid chloride Cl—COOR⁶.

The reaction is preferably conducted in a solvent, for exampledichloromethane, toluene and/or tetrahydrofuran, at a temperaturebetween −10° C. and +30° C.

1-phenyl-3-dimethylaminopropane compounds of formula I, in which R⁵ is Hand R⁴ is a meta-phosphate group, meta-carbonate group, meta-carbamategroup or meta-carboxylate group, can be obtained by the reaction of thecorresponding 1-(3-hydroxyphenyl)-3-dimethylaminopropane compounds offormula I in the form of their alkali salts with an alkali salt of adialkyl chlorophosphate, with an alkyl chloroformate, with an arylisocyanate or with a carboxylic acid chloride. These reactions areusually conducted in a solvent, for example toluene, dichloromethane,diethyl ether and/or tetrahydrofuran, at temperatures between −15° C.and +110° C. (Drugs of the Future 16, 443 (1991); J. Med. Chem. 30, 2008(1987) and 32, 2503 (1989); J. Org. Chem. 43, 4797 (1978); TetrahedronLett. 1977, 1571; J. Pharm. Sci. 57, 774 (1968)).

The compounds of formula I can be converted in a known manner into theirsalts with physiologically acceptable acids, for example hydrochloricacid, hydrobromic acid, sulfuric acid, methanesulfonic acid, formicacid, acetic acid, oxalic acid, succinic acid, tartaric acid, mandelicacid, fumaric acid, lactic acid, citric acid, glutamic acid and/oraspartic acid. Salt formation is preferably effected in a solvent, forexample diethyl ether, diisopropyl ether, alkyl acetates, acetone and/or2-butanone. Moreover, trimethylchlorosilane in aqueous solution issuitable for the preparation of hydrochlorides.

1-phenyl-3-dimethylaminopropane compounds of formula I aretoxicologically harmless, so that they are suitable as pharmaceuticalactive ingredients in drugs.

Accordingly, the present invention also relates to the use of a1-phenyl-3-dimethylaminopropane compound of formula I as apharmaceutical active ingredient. Compounds of formula I are preferablyused for the treatment of pain.

In addition to at least one 1-phenyl-3-dimethylaminopropane compound offormula I, the analgesics according to the invention may containcarriers, fillers, solvents, diluents, colorants and/or binders. Theselection of auxiliary substances and of the amounts of the same to beused depends on whether the drug is to be administered orally,intravenously, intraperitoneally, intradermally, intramuscularly,intranasally or locally, for example for infections of the skin, of themucous membranes or of the eye. Preparations in the form of tablets,dragees, capsules, granules, drops, liquids and syrups are suitable fororal application. Solutions, suspensions, readily reconstitutable drypreparations, and sprays are suitable for parenteral, topical andinhalative applications. Compounds of formula I according to theinvention in a deposit in dissolved form or in a patch, optionally withthe addition of a skin penetration promoter, are suitable preparationsfor percutaneous application. Forms of preparations which can beadministered orally or percutaneously may effect delayed release of thecompounds of formula I according to the invention.

The amount of active ingredient to be administered to patients variesdepending on the patient's weight, on the manner of administration, theindication and the degree of severity of the illness. 50 to 500 mg/kg ofat least one 1-phenyl-3-dimethylaminopropane compound of formula I areusually administered.

EXAMPLES

The yields of the compounds prepared have not been optimised.

All temperatures are uncorrected.

Unless otherwise indicated, petroleum ether with a boiling point of50-70° C. was used. The term “ether” denotes diethyl ether.

Silica gel 60 (0.040-0.063 mm) manufactured by E. Merck, Darmstadt, wasused as the stationary phase for column chromatography.

This layer chromatography investigations were conducted usingprefabricated silica gel 60 F 254 HPTLC plates manufactured by E. Merck,Darmstadt.

Racemate separation was effected on a Chiracel OD column.

The mixture ratios of the mobile phases for all chromatographicinvestigations are expressed as volume/volume.

RT denotes room temperature; m.p. denotes melting point.

Example 1

(2RS,3RS)-1-dimethylamino-3-(3-methoxyphenyl)-2-methylpentan-3-olHydrochloride(1)

207.63 g (1.11 mole) 3-bromoanisole dissolved in 400 ml drytetrahydrofuran were added drop-wise to 26.99 g (1.11 mole) magnesiumturnings in 150 ml dry tetrahydrofuran so that the reaction mixtureboiled gently. After the addition of 3-bromoanisole was complete themixture was heated under reflux for one hour and thereafter was cooledto 5-10° C. 128.30 g (0.89 mole) 1-dimethylamino-2-methylpentan-3-onedissolved in 400 ml tetrahydrofuran were added at this temperature. Thereaction mixture was allowed to stand overnight and then cooled again to5-10° C. The Grignard solution was decomposed by the addition of 300 mlof 20% ammonium chloride solution. The reaction mixture was diluted with400 ml ether, the organic phase was separated off and the aqueous phasewas extracted twice with 250 ml ether. The combined organic phases weredried over sodium sulphate. After removing the solvent by distillation,the residue (212 g) was taken up in 3200 ml 2-butanone and added to120.60 g (1.11 mole) trimethylchlorosilane and 20 ml water. 121.5 g ofhydrochloride (1) (38% theoretical) with a melting point of 198-199° C.crystallised out at 4-5° C.

Example 2

Enantiomers of (1):

-   (−)-(2S,3S)-1-dimethylamino-3-(3-methoxyphenyl)-2-methylpentan-3-ol    Hydrochloride(−1)    and-   (+)-(2R,3R)-1-dimethylamino-3-(3-methoxyphenyl)-2-methylpentan-3-ol    Hydrochloride(+1).

The base was released from (1) with dichloromethane/sodium hydroxidesolution. After drying the solution dichloromethane was distilled offunder vacuum. The racemate was then separated on the chiral HPLC column.The hydrochlorides, which had a melting point of 150-151° C., wereprepared from the enantiomers obtained by reaction withtrimethylchlorosilane/water in 2-butanone.

(−1):

yield: 42% theoretical

[α]_(D) _(RT) =−31.8° (c=0.99; methanol)

(+1):

yield: 41% theoretical

[α]_(D) _(=RT) +33.0° (c=0.96; methanol)

Example 3

(2RS,3RS)-3-(3,4-dichlorophenyl)-1-dimethylamino-2-methylpentan-3-olHydrochloride (2)

39 g of crude mixture were prepared analogously to Example 1 from 15 g(105 mmol) 1-dimethylamino-2-methylpentan-3-one, 35.5 g (157 mmole)4-bromo-1,2-dichlorobenzene and 3.8 g (157 mmole) magnesium turnings.This mixture was introduced on to a 7×40 cm column packed with silicagel and eluted with 4:1 ethyl acetate/methanol. 14.9 g of base wereobtained, from which 11.2 g of hydrochloride (2) (31% theoretical) witha melting point of 183-184° C. were obtained withtrimethylchlorosilane/water in 2-butanone/diisopropyl ether.

Example 4

(2RS,3RS)-3-(3-isopropoxyphenyl)-1-dimethylamino-2-methylpentan-3-olHydrochloride (3)

25 g of crude mixture were prepared analogously to Example 1 from 14.3 g(100 mmol) 1-dimethylamino-2-methylpentan-3-one, 20.0 g (157 mmole)1-bromo-3-isopropoxybenzene and 2.79 g (115 mmole) magnesium turnings.This mixture was introduced on to a 7×40 cm column packed with silicagel and eluted with 15:1 ethyl acetate/methanol. 9.0 g of base wereobtained, from which 8.3 g of hydrochloride (3) (26% theoretical) with amelting point of 133-134° C. were obtained withtrimethylchlorosilane/water in 2-butanone.

Example 5

(2RS,3RS)-3-(3-chlorophenyl)-1-dimethylamino-2-methylpentan-3-olHydrochloride (4)

63 g of crude mixture were obtained under the conditions cited forExample 1 from 38.0 g (270 mmole) 1-dimethylamino-2-methylpentan-3-one,74.7 g (390 mmol) 1 -bromo-3-chlorobenzene and 9.50 g (390 mmole)magnesium turnings. This mixture was introduced on to a 7×45 cm columnpacked with silica gel and eluted with 7:1 diisopropyl ether/methanol.12.8 g of base were obtained, from which 10.8 g of hydrochloride (4)(14% theoretical) with a melting point of 160-162° C. were obtained withtrimethylchlorosilane/water in 2-butanone/ether.

Example 6

(2RS,3RS)-1-dimethylamino-2-methyl-3-(3-trifluoromethylphenyl)-pentan-3-olHydrochloride(5)

21.2 g of crude mixture were obtained under the conditions cited forExample 1 from 14.3 g (100 mmole) 1-dimethylamino-2-methylpentan-3-one,29.3 g (130 mmole) 1-bromo-3-trifluoromethylbenzene and 3.2 g (130mmole) magnesium turnings. This mixture was introduced on to a 6×40 cmcolumn packed with silica gel and eluted with 10:1 diisopropylether/methanol. 9.1 g of base were obtained, from which 7.8 g ofhydrochloride (5) (18.5% theoretical) with a melting point of 189-190°C. was obtained with trimethylchlorosilane/water in 2-butanone.

Example 7

(2RS,3RS)-1-dimethylamino-2-methyl-3-(3-m-tolyl)-pentan-3-olHydrochloride (6)

75 g of crude mixture were obtained as in Example 1 from 47.3 g (330mmole) 1-dimethylamino-2-methylpentan-3-one, 64.6 g (400 mmole)3-bromotoluene and 9.72 g (400 mmole) of magnesium turnings. Thismixture was introduced on to a 7×50 cm column packed with silica gel andeluted with 7:1 diisopropyl ether/methanol. 24.3 g of base wereobtained, from which 21.5 g of hydrochloride (6) (24% theoretical) witha melting point of 154-155° C. were obtained withtrimethylchlorosilane/water in 2-butanone.

Example 8

(2RS, 3RS)-1-dimethylamino-3-(3-fluorophenyl)-2-methylpentan-3-olHydrochloride (7)

70 g of crude mixture were obtained under the conditions cited forExample 1 from 54.0 g (380 mmole) 1-dimethylamino-2-methylpentan-3-one,82.5 g (470 mmole) 1-bromo-3-fluorobenzene and 9.23 g (470 mmole)magnesium turnings. This mixture was introduced on to a 7×50 cm columnpacked with silica gel and eluted with 1:1 ethyl acetate/methanol. 13.0g of base were obtained, from which 11.2 g of hydrochloride (7) (11.5%theoretical) with a melting point of 145-146° C. was obtained withtrimethylchlorosilane/water in 2-butanone.

Example 9

(2RS,3RS)-3-(3-difluoromethylphenyl)-1-dimethylamino-2-methylpentan-3-olHydrochloride(8)

7.0 g (34 mmole) 1-bromo-3-difluoromethylbenzene, prepared from3-bromobenzaldehyde and diethylaminosulphur trifluoride indichloromethane according to Org. React. 35, 513 (1988) were dissolvedin 110 ml of dry tetrahydrofuran and cooled to −75° C. After theaddition of 21.12 ml (34 mmole) of a 1.6 molar solution ofn-butyllithium in hexane the mixture was stirred for one hour at −75° C.4.8 g (34 mmole) 1-dimethylamino-2-methylpentan-3-one dissolved in 15 mlof dry tetrahydrofuran were then added dropwise. The reaction mixturewas warmed to room temperature over 2.5 hours.

Work-up was effected by the drop-wise addition of 65 ml of 5%hydrochloric acid with cooling in an ice bath, so that the internaltemperature did not exceed 15° C. After phase separation the organicphase was extracted with 40 ml of 5% hydrochloric acid. The combinedaqueous phases were washed twice with 50 ml ether. In order to releasethe base, the mixture was added to concentrated sodium hydroxidesolution and extracted with dichloromethane. 7.8 g of crude product wereobtained in this manner and was introduced on to a 7×40 cm column packedwith silica gel. Elution with 1:1 ethyl acetate/methanol gave 4.89 g ofbase, from which 4.6 g of hydrochloride (8) (44% theoretical) with amelting point of 194-195° C. was obtained withtrimethylchlorosilane/water in 2-butanone.

Example 10

(2RS,3RS)-1-dimethylamino-2-methyl-3-(3-methylsulphanylphenyl)-pentan-3-olHydrochloride(9)

38 g of crude mixture were obtained under the conditions cited forExample 1 from 17.6 g (123 mmole) 1-dimethylamino-2-methylpentan-3-one,25.0 g (123 mmole) 1-bromo-3-methylsulphanylbenzene and 3.0 g (123mmole) magnesium turnings. This mixture was introduced on to a 7×40 cmcolumn packed with silica gel and eluted with 10:1 ethylacetate/methanol. 8.35 g of base were obtained, from which 7.2 g ofhydrochloride (9) (19% theoretical) with a melting point of 159-160° C.were obtained with trimethylchlorosilane/water in 2-butanone.

Example 11

(2RS,3RS)-3-benzofuran-6-yl-1-dimethylamino-2-methylpentan-3-olHydrochloride(10)

3.45 g (18 mmole) 6-bromobenzofurane (prepared according to EP 355 827)and 6 ml 1,2-dibromoethane, dissolved in 60 ml dry ether, were addeddrop-wise over 1.5 hours to 2.12 g (87 mmole) magnesium turnings in 30ml dry ether; after the addition the mixture was heated under reflux for30 minutes. Thereafter, 2.5 g (18 mmole)1-dimethylamino-2-methylpentan-3-one dissolved in 7.5 ml ether was addeddrop-wise over 1.5 hours whilst cooling in an ice bath to maintain aninternal temperature of 5-10° C. The reaction mixture was allowed tostand for 12 hours at room temperature, and was then cooled again to5-10° C. and added to 35 ml of 20% aqueous ammonium chloride solution.After phase separation, the aqueous phase was extracted twice with 50 mlether. The combined organic phases were dried over sodium sulphate.After removing the solvent by distillation the residue (3.9 g) wasintroduced on to a 5×16 cm column packed with silica gel 0.95 g of basewere obtained by elution with 7:1 diisopropyl ether/methanol, from which0.82 g of hydrochloride (10) (15.5% theoretical) with a melting point of162° C. were obtained with trimethylchlorosilane/water in ethylacetate/2-butanone.

Example 12

(2RS,3RS)-1-dimethylamino-2-methyl-3-(4-trifluoromethylphenyl)-pentan-3-olHydrochloride (11)

44 g of crude mixture were obtained as in Example 1 from 20 g (140mmole) 1-dimethylamino-2-methylpentan-3-one, 31.5 g (140 mmole)1-bromo-4-trifluoromethylbenzene, 16.5 g (680 mmole) magnesium turningsand 47 ml 1,2-dibromomethane. This mixture was introduced on to a 7×50cm column packed with silica gel and eluted with 5:1 ethylacetate/methanol. 16.4 g of base were obtained, from which 12.3 g ofhydrochloride (11) (27% theoretical) with a melting point of 170-171° C.were obtained with trimethylchlorosilane/water in 2-butanone.

Example 13

(3RS)-1-dimethylamino-3-(3-methoxyphenyl)-hexan-3-ol Hydrochloride (12)

18.5 g of crude mixture were obtained as in Example 1 from 10 g (70mmole) 1-dimethylamino-hexan-3-one, 18.7 g (100 mmole)1-bromo-3-methoxybenzene and 2.3 g (100 mmole) magnesium turnings. Thismixture was introduced on to a 6×50 cm column packed with silica gel andeluted with 1:1 ethyl acetate/methanol. 6.84 g of base were obtained,from which 6.15 g of hydrochloride (12) (32% theoretical) with a meltingpoint of 179-180° C. were obtained with trimethylchlorosilane/water in2-butanone.

Example 14

(3RS)-1-dimethylamino-3-(3-methoxyphenyl)-heptan-3-ol Hydrochloride (13)

17.3 g of crude mixture were obtained as in Example 1 from 10 g (64mmole) 1-dimethylamino-heptan-3-one, 15.9 g (157 mmole)1-bromo-3-methoxybenzene and 2.06 g (85 mmole) magnesium turnings. Thismixture was introduced on to a 6×40 cm column packed with silica gel andeluted with ethyl acetate. 5.4 g of base were obtained, from which 4.1 gof hydrochloride (13) (21% theoretical) with a melting point of 150° C.were obtained with trimethylchlorosilane/water in 2-butanone.

Example 15

(3RS)-1-dimethylamino-3-(3-methoxyphenyl)-4,4-dimethylpentan-3-olHydrochloride(14)

37 g of crude mixture were obtained as in Example 1 from 18.6 g (118mmole) 1-dimethylamino-4,4-dimethylpentan-3-one, 28.4 g (152 mmole)1-bromo-3-methoxybenzene and 3.7 g (152 mmole) magnesium turnings. Thismixture was introduced on to a 7×40 cm column packed with silica gel andeluted with 5:1 ethyl acetate/methanol. 2.2 g of base were obtained,from which 1.8 g of hydrochloride (14) (5% theoretical) with a meltingpoint of 213° C. were obtained with trimethylchlorosilane/water in2-butanone.

Example 16

(2RS,3RS)-4-dimethylamino-2-(3-methoxyphenyl)-3-methylbutan-3-olHydrochloride(15)

21 g of crude mixture were obtained as in Example 1 from 5.3 g (41mmole) 4-dimethylamino-3-methylbutan-3-one, 23.0 g (123 mmole)1-bromo-3-methoxybenzene and 3.0 g (123 mmole) magnesium turnings. Thismixture was introduced on to a 4.5×27 cm column packed with silica geland eluted with 4:1 ethyl acetate/methanol. 4.0 g of base were obtained,from which 3.6 g of hydrochloride (15) (32%) theoretical) with a meltingpoint of 124° C. were obtained with trimethylchlorosilane/water in2-butanone.

Example 17

Enantiomers of (15):

-   (−)-(2S,3S)-4-dimethylamino-2-(3-methoxyphenyl)-3-methylbutan-3-ol    Hydrochloride (−15)    and-   (+)-(2R,3R)-4-dimethylamino-2-(3-methoxyphenyl)-3-methylbutan-3-ol    Hydrochloride(+15).

The base was released from hydrochloride (15), which was prepared as inExample 16, with dichloromethane/sodium hydroxide solution. After dryingand removal of dichloromethane by distillation, the racemate was thenseparated into the enantiomers on a chiral HPLC column. Thehydrochlorides were obtained from the enantiomers withtrimethylchlorosilane/water in 2-butanone.

(−15):

yield: 41% theoretical

m.p.: 117-118° C.

[α]_(D) _(RT) =−38.6° (c=1.05; methanol)

(+15):

yield: 41% theoretical

m.p.: 118-119° C.

[α]_(D) _(RT) =+41.0° (c=1.01; methanol)

Example 18

(2RS,3RS)-3-(3-dimethylamino-1-ethyl-1-hydroxy-2-methylpropyl)-phenolHydrochloride(16).

The base was released from compound (1), which was prepared as inExample 1, with dichloromethane/sodium hydroxide solution. After dryingthe solution, dichloromethane was removed by distillation. 4.3 g (17mmole) of base were dissolved in 25 ml dry toluene and slowly addeddrop-wise to 71 ml (85 mmole) of a 1.2 molar solution ofdiisobutylaluminium hydride in toluene. When the addition was complete,the mixture was heated for 8 hours under reflux and then cooled to roomtemperature. The reaction mixture was diluted with 25 ml toluene. 9.4 mlethanol followed by 9.4 ml water were added drop-wise whilst cooling inan ice bath. After stirring for one hour whilst cooling in the ice baththe reaction mixture was freed from aluminium salts by filtration, andthe residue was washed three times with 50 ml toluene in each case.Thereafter the combined organic phases were dried and toluene wasremoved by distillation. 3.95 g of hydrochloride (16) (85% theoretical)with a melting point of 213-214° C. were obtained from the base withaqueous hydrochloric acid solution in acetone.

Example 19

Enantiomers of (16):(-) (2S,3S)1S,2S)-3-(dimethylamino-1-ethyl-1-hydroxy-2-methylpropyl)-phenolHydrochloride (-16) and(+) (2S,3S1R,2R)-3-(dimethylamino-1-ethyl-1-hydroxy-2-methylpropyl)-phenolHydrochloride (+16)

The enantiomers (−16) and (+16) were prepared under the conditions citedin Example 2.

(−16):

yield: 85% theoretical

m.p.: 208-209° C.

[α]_(D) _(RT) =−34.6° (c=0.98; methanol)

(+16):

yield: 85% theoretical

m.p.: 206-207° C.

[α]_(D) _(RT) =+34.4° (c=1.06; methanol)

Example 20

(1RS,2RS)-3-(3-dimethylamino-1-hydroxy-1,2-dimethylpropylphenolHydrochloride(17)

Compound (17) was prepared under the conditions cited in Example 18starting from methoxy compound (15) which was obtained as in Example 16.

Yield: 85% theoretical

m.p.: 232° C.

Example 21

Enantiomers of (17):

-   (−)-(1S,2S)-3-(3-dimethylamino-1-hydroxy-1,2-dimethylpropyl)-phenol    Hydrochloride(−17)    and    (+)-(1R,2R)-3-(3-dimethylamino-1-hydroxy-1,2-dimethylpropyl)-phenolhydrochloride(+17)

The enantiomers (−17) and (+17) were prepared under the conditions citedin Example 2.

(−17):

yield: 82% theoretical

m.p.: 204-205° C.

[α]_(D) _(RT) =−42.0° (c=0.94; methanol)

(+17):

yield: 83% theoretical

m.p.: 204-205° C.

[α]_(D) _(RT) =+41.2° (c=1.01; methanol)

Example 22

(+)-(1R,2R)-3-(3-dimethylamino-1-ethyl-1-fluoro-2-methylpropyl)-phenolHydrochloride(+18)1st Step

(+)-(1R,2R)-3-(3-benzyloxyphenyl)-1-dimethylamino-2-methylpentan-3-ol(+19)

The base was released with dichloromethane/sodium hydroxide solutionfrom enantiomer (+16) obtained as in Example 19, and dichloromethane wasremoved by distillation after drying the solution. 5.3 g (22 mmole) ofbase were dissolved in 27 ml of dry dimethylformamide and added inseveral portions to 1.2 g of 50% sodium hydride. After the addition of2.8 ml (24 mmole) benzoyl chloride the mixture was heated for threehours at 70° C. The reaction mixture was then cooled to room temperatureand poured on to an ice/water mixture. It was extracted three times with70 ml ether in each case. After drying the combined organic phases oversodium sulphate, the solvent was distilled off and the residue wasintroduced on to a 4.5×30 cm column packed with silica gel. 6.8 g ofbase (+19) (92% theoretical) were obtained as a light yellow, highlyviscous oil by elution with diisopropyl ether/methanol.2nd Step

(+)-(2R,3R)-[3-(3-benzyloxyphenyl)-3-fluoro-2-methylpentyl]-dimethylamine(+20)

6.8 g (21 mmole) of (+19), dissolved in 80 ml dichloromethane, wereadded dropwise at −20° C. to a solution of 3.7 g (23 mmole)diethylaminosulphur trifluoride in 30 ml of dry dichloromethane. Afterthe addition was complete, the mixture was stirred for 30 minutes atthis temperature and then warmed to room temperature. After stirring fora further one hour at room temperature, the mixture was cooled to 0-5°C. and hydrolysed with 50 ml water. After phase separation, the aqueousphase was extracted twice with 50 ml dichloromethane. The combinedorganic phases were dried and freed from solvent by distillation undervacuum. The crude mixture obtained (8.04 g) was introduced on to a 6×50cm column packed with silica gel and eluted with 1:1 ethylacetate/methanol. 3.04 g of base (+20) (40% theoretical) were obtainedas a light yellow, viscous oil.

3rd Step:

(+)-(1R,2R)-3-(3-dimethylamino-1-ethyl-1-fluoro-2-methylpropyl)-phenolHydrochloride(+18)

3.0 g (91 mmole) of (+20) were dissolved in 15 ml of dry methanol andadded to 0.44 g palladium on activated carbon (10% Pd) in ahydrogenation apparatus. 215 ml hydrogen was consumed after stirring forthree hours at room temperature. The catalyst was removed by filtration,and the methanol was removed by distillation. 2.22 g of base wereobtained, from which 2.0 g of hydrochloride (+18) (79% theoretical) wereobtained with trimethylchlorosilane/water in 2-butanone.

m.p.: 174-176° C.

[α]_(D) _(RT) =+29.5° (c=1.08; methanol)

Example 23

(−)-(1S,2S)-3-(3-dimethylamino-1-ethyl-1-fluoro-2-methylpropyl)-phenolHydrochloride(−18)

Enantiomer (−18) was obtained in a yield of 29% theoretical fromenantiomer (−16) obtained as in Example 19, under the conditions citedin Example 22.

m.p.: 170-172° C.

[α]_(D) _(RT) =−28.4° (c=1.03; methanol)

Example 24

(+)-(1S,2R 2S)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)-phenolhydrochloride (+21)1st Step:

(+)-(2R,3R)-[3-chloro-3-(-3-methoxyphenyl)-2-methylpentyl]-dimethylamineHydrochloride(+22)

10 g (35 mmole) of (+1), prepared as in Example 2, were added to 10 mlthionyl chloride at room temperature. Nitrogen was subsequently passedover the reaction mixture for two hours to remove excess thionylchloride. After a fresh addition of 10 ml thionyl chloride the reactionmixture was allowed to stand for 12 hours before excess thionyl chloridewas again removed over a period of 2.5 hours by means of a stream ofnitrogen. After drying, the residue was dissolved in 10 ml of ice-cold2-butanone and mixed with stirring with 200 ml ether and then with 140ml diisopropyl ether. The supernatant solvent phase was decanted off andthe remaining oil was again taken up in 10 ml 2-butanone. After theaddition of seed crystals, 300 ml diisopropyl ether were added drop-wisewith vigorous stirring over three hours, whereupon the hydrochloridecrystallised out. 9.8 g of (22) (91% theoretical) were obtained.

m.p.: 120° C. (decomposition)

[α]_(D) _(RT) =+24.7° (c=1.01; methanol)2nd Step:

(+)-(2R 2S, 3S)-[3-(3-methoxyphenyl)-2-methylpentyl]-dimethylamineHydrocholoride (+23)

46 g of dried zinc chloride were dissolved in 580 ml of dry ether andsubsequently added drop-wise to a slurry of 31 g sodium borohydride in1800 ml ether. After stirring for 12 hours, 500 ml were removed bydecantation from the zinc borohydride suspension obtained and addeddrop-wise to 9.8 g (32 mmole) of (+22) in 200 ml of dry ether. Thereaction mixture was stirred for 72 hours at room temperature and thenadded drop-wise to 40 ml of a saturated ammonium chloride solution withcooling in an ice bath. After phase separation, the ether phase waswashed twice with saturated brine; after drying over sodium sulphate thesolvent was distilled off under vacuum. 7.3 g of an amine-borane complexwere obtained, which were dissolved in 100 ml of dry methanol to isolatethe free base. After the addition of 7.5 g triphenylphosphine themixture was heated for 18 hours under reflux. After removing the solventby distillation the residue was added to 100 ml of 5% hydrochloric acid,and the hydrochloric acid phase was subsequently washed twice with 50 mlether. Thereafter the hydrochloric acid phase was made alkaline withconcentrated sodium hydroxide solution whilst cooling in an ice bath,and was solvent-extracted twice with 50 ml dichloromethane. After dryingthe combined organic phases over sodium sulphate the solvent wasdistilled off under vacuum and the remaining residue (5.2 g) was takenup in 2-butanone. After the addition of trimethylchlorosilane/water, 4.3g of hydrochloride (+23) (50% theoretical) crystallised out.

m.p.: 163-164° C.

[α]_(D) _(RT) =+25.20 (c=0.95; methanol)

3rd Step:

(+)-(1S,2R 2S)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)-phenolHydrochloride(+21)

4.3 g (15 mmole) of (+23) from step 2 were added to 100 ml ofconcentrated hydrobromic acid. The mixture was then heated under refluxfor two hours. After cooling to room temperature the reaction mixturewas concentrated under the vacuum from a water pump. The residue wastreated with concentrated sodium hydrogen carbonate solution until analkaline reaction was obtained. After extracting twice with 50 mldichloromethane in each case the combined organic phases were dried oversodium sulphate. Dichloromethane was then distilled off under vacuum andthe residue (4 g) was taken up in 2-butanone. After the addition oftrimethylchlorosilane/water, 3.8 g of hydrochloride (+21) (98%theoretical) crystallised out.

m.p.: 194-196° C.

[α]_(D) _(RT) =+24.5° (c=1.10; methanol)

Example 25

(-)-(1R,2S 2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)-phenolhydrochloride(-21)

Enantiomer (−21) was obtained in 45% yield under the conditions cited inExample 24 from (−1), which was prepared as in Example 2.

m.p.: 168-170° C.

[α]_(D) _(RT) =−27.5° (c=0.97; methanol)

Example 26

(+)-(1R,2R)-aceticacid-3-dimethylamino-1-ethyl-1-(3-methyoxyphenyl)-2-methylpropyl EsterHydrochloride(+24)

The base was released from enantiomer (+1), which was prepared as inExample 2, with dichloromethane/sodium hydroxide solution. After dryingthe solution, dichloromethane was removed by distillation. 3.0 g (39mmole) acetyl chloride were added drop-wise, whilst cooling in an icebath, to 10 g (35 mmole) of the base obtained, which had been taken upin 150 ml of dry dichloromethane. After the addition of acetyl chloridewas complete, the reaction mixture was warmed to room temperature, andafter stirring for two hours was mixed with 100 ml of saturated sodiumhydrogen carbonate solution. The organic phase was separated from theaqueous phase and the aqueous phase was extracted twice with 50 mldichloromethane. The organic phases were combined and dried over sodiumsulphate. After removing the solvent by distillation, 13.4 g crudemixture were obtained, from which 10.7 g, of hydrochloride (+24) (93%theoretical) was obtained with trimethylchlorosilane/water in2-butanone/ethyl acetate.

m.p.: 153° C.

[α]_(D) _(RT) =−17.3° (c=1.04; methanol)

Example 27

(1RS)-1-(1-dimethylaminomethyl-cyclohexyl)-1-(3-methoxyphenyl)-propan-1-olHydrochloride(25)1st Step:

(1RS)-1-(1-dimethylaminomethyl-cyclohexyl)-(3-methoxyphenyl)-methanolHydrochloride(26)

44 g crude mixture was obtained from 25 g (150 mmole)1-dimethylaminomethyl-cyclohexane carbaldehyde, 32.9 g (180 mmole)1-bromo-3-methoxybenzene and 4.3 g (180 mmole) magnesium turnings, underthe conditions cited in Example 1. This mixture was introduced on to a7×40 cm column packed with silica gel and eluted with 4:1 diisopropylether/methanol. 38 g of base were obtained, from which 40 g ofhydrochloride (26) (85% theoretical) with a melting point of 235° C.were obtained with trimethylchlorosilane/water in 2-butanone.2nd Step:

(1RS)-(1-dimethylaminomethyl-cyclohexyl)-(3-methoxyphenyl)-methanoneHydrochloride(27)

The base was released from (26) with dichloromethane/sodium hydroxidesolution and after drying the solution dichloromethane was removed bydistillation. 8.3 g (30 mmole) of base were dissolved in 30 ml n-hexaneand added drop-wise to a suspension consisting of 95 g pyridiniumchlorochromate (prepared according to Synthesis 1980, 223) absorbed onneutral alumina. After stirring for 72 hours at room temperature thereaction mixture was mixed with 120 ml dichloromethane, stirred for afurther 2 hours and then filtered through 30 g alumina. The filterresidue was washed three times by decantation with 50 ml dichloromethaneand ether in each case. The organic phases were combined with thefiltrate and freed from solvent by distillation. The residue obtainedwas taken up in 60 ml of 2 Normal sodium hydroxide solution andextracted four times with 20 mg ethyl acetate in each case. After dryingthe combined organic phases, the solvent was removed by distillation.4.8 g crude mixture were obtained, which was introduced on to a 6×30 cmcolumn packed with silica gel and eluted, firstly with ethyl acetate,then with 9:1 ethyl acetate/methanol and finally with 4:1 ethylacetate/methanol. 3.8 g of base were obtained, from which 3.1 g ofhydrochloride (27) (33% theoretical) with a melting point of 174° C.were obtained with trichlorosilane/water in 2-butanone.

3rd Step:

(1RS)-1-(1-dimethylaminomethyl-cyclohexyl)-1-(3-methoxyphenyl)-propan-1-olHydrochloride(25)

3.0 g crude mixture was obtained, under the conditions cited in Example1, from 2.8 g (10 mmole) of (27) in the form of the base, 1.4 g (13mmole) bromoethane and 0.32 g (13 mmole) magnesium turnings, using etheras the solvent. This mixture was introduced on to a 3×20 cm columnpacked with silica gel and eluted with 19:1 diisopropyl ether/methanol,2.1 g of base were obtained, from which 1.9 g of hydrochloride (25) (55%theoretical) with a melting point of 230° C. were obtained withtrichlorosilane/water in 2-butanone/ethyl acetate.

Example 28

(−)-(2R,3S)-{3[3-(p-isopropyl-phenyl-carbamoyl)-oxy-phenyl]-2-methylpentyl-dimethylamineHydrochloride(−28)

The base was released from enantiomer (+21), which was prepared as inExample 24, with dichloromethane/sodium hydroxide solution, and afterdrying the solution dichloromethane was removed by distillation. 2.2 g(10 mmole) of the base obtained were dissolved in 20 ml of dry tolueneand mixed with 1.8 g (11 mmole) 4-isopropylphenyl isocyanate. Afterstirring for 20 hours at room temperature the toluene was removed bydistillation. The residue was reacted with trimethylchlorosilane/waterin n-propyl acetate to form 3.2 g of hydrochloride (−28) (76%theoretical).

m.p.: 151-152° C.

[α]_(D) _(RT) =−5.2° (c=1.11; methanol)

Pharmacological Investigations

Writhing Test on Mice

The analgesic effectiveness of the compounds according to the inventionwas investigated in the phenylquinone-induced writhing test, modifiedaccording to I. C. Hendershot, J. Forsaith in J. Pharmacol. Exptl. Ther.125, 237 (1959), on mice. Male NMRI mice with a weight between 25 and 30g were used for this purpose. For each dose of substance, each 10animals received, 30 minutes after the oral administration of a compoundaccording to the invention, 0.3 ml per mouse of an 0.02% aqueousphenylquinone solution (phenylbenzoquinone manufactured by Sigma,Deisenhofen; solution prepared with the addition of 5% ethanol and kepton a water bath at 45° C.) administered intraperitoneally. Thereafterthe animals were placed individually in observation cages. The number ofpain-induced stretching movements (writhing reaction-straightening ofthe body with stretching of the rear extremities) was counted with theaid of a push-button counter. The Ed₅₀ value (effective dose with 50%inhibition of writhing reaction) was calculated with a 95% confidencelimit by means of regression analysis (evaluation program supplied byMartens EDV-Service, Eckental) from the dose-dependent decrease in thewrithing reaction, by comparison with mice tested in parallel to whichonly phenylquinone had been administered. All the compounds according tothe invention which were investigated exhibited a pronounced analgesiceffect. The results are summarized in the following Table:

TABLE Writhing inhibition Compound % Inhibition according to ED₅₀ 25mg/kg Example the invention [mg/kg per os] per os 1 (1) 5.8 2 (−1) 22.32 (+1) 1.1 3 (2) 13.2 4 (3) −81.3 5 (4) 15.5 6 (5) 8.3 7 (6) 11.8 8 (7)27.3 9 (8) 12.9 10 (9) 12.8 11 (10) 12.9 13 (12) 19.9 15 (14) 10.5 16(15) 3.8 17 (+15) −95.2 18 (16) −100.0 19 (−16) 16.1 19 (+16) 1.0 20(17) −87.0 21 (−17) −58.3 21 (+17) −97.2 22 (+18) 15.7 24 (+21) 1.9

The foregoing description and examples have been set forth merely toillustrate the invention and are not intended to be limiting. Sincemodifications of the disclosed embodiments incorporating the spirit andsubstance of the invention may occur to persons skilled in the art, theinvention should be construed to include all variations within the scopeof the appended claims and equivalents thereof.

What is claimed is:
 1. An isolated 1-phenyl-3-dimethylaminopropanediastereoisomer having a configuration corresponding to formula Ia′:

X represents OH, F, Cl, H or an OCOR⁶ group in which R⁶ is a C₁₋₃-alkylgroup; R¹ is a C₁₋₄-alkyl group; R² represents H or a C₁₋₄-alkyl group,and R³ is different from R² and represents H or a straight chainC₁₋₄-alkyl group, and R⁵ represents H, and R⁴ represents meta-O—Z, whereZ is H, C₁₋₃-alkyl, PO(OC₁₋₄alkyl)₂, CO(OC₁₋₅-alkyl),CONH—C₆H₄—(C₁₋₃-alkyl) or CO—C₆H₄—R⁷, in which R⁷ is ortho-OCOC₁₋₃-alkylor meta- or para-CH₂N(R⁸)₂, where R⁸ is C₁₋₄-alkyl or 4-morpholino, orR⁴ represents meta-S-C₁₋₃-alkyl, meta-Cl, meta-F, meta-CR⁹R¹⁰R¹¹,ortho-OH, ortho-O—C₂₋₃-alkyl, para-F or para-CR⁹R¹⁰R¹¹, where R⁹, R¹⁰and R¹¹ independently represent H or F, or R⁵ represents para-Cl,para-F, para-OH or para-O—C₁₋₃-alkyl, and R⁴ represents meta-Cl, meta-F,meta-OH or meta-O—C₁₋₃-alkyl, or R⁴ and R⁵ together represent3,4-OCH═CH— or 3,4-OCH═CHO—; or a salt thereof with a physiologicallyacceptable acid.
 2. An isolated 1-phenyl-3-dimethylaminopropanediastereoisomer according to claim 1, wherein X represents OH, F, Cl orH; R¹ represents a C₁₋₄-alkyl group; R² represents H or CH₃; R³ isdifferent from R² and represents H or CH₃, and R⁵ represents H, and R⁴represents meta-OC₁₋₃-alkyl, meta-OH, meta-S—C₁₋₃-alkyl, meta-F,meta-Cl, meta-CH₃, meta-CF₂H, meta-CF₃ or para-CF₃, or R⁵ representspara-Cl or para-F, and R⁴ represents meta-Cl or meta-F, or R⁴ and R⁵together represent 3,4-OCH═CH—.
 3. An isolated1-phenyl-3-dimethylaminopropane diastereoisomer according to claim 1,wherein X represents OH, F, Cl or an OCOR⁴ group in which R⁶ is aC₁₋₃-alkyl group.
 4. An isolated 1-phenyl-3-dimethylaminopropanediastereoisomer according to claim 1, wherein R² is C₁₋₄-alkyl.
 5. Anisolated 1-phenyl-3-dimethylaminopropane diastereoisomer according toclaim 1, wherein R⁹, R¹⁰ and R¹¹ represent F.
 6. An isolated1-phenyl-3-dimethylaminopropane diastereoisomer having a configurationcorresponding to the formula Ia,

wherein X represents OH, F, Cl, H or an OCOR⁶ group in which R⁶ is aC₁₋₃-alkyl group; R¹ is a C₁₋₄-alkyl group; R² represents a C₁₋₄-alkylgroup, and R⁵ represents H, and R⁴ represents meta-O—Z, where Z is H,C₁₋₃-alkyl, PO(OC₁₋₄alkyl)₂, CO(OC₁₋₅-alkyl), CONH—C₆H₄—(C₁₋₃-alkyl) orCO—C₆H₄—R⁷, in which R⁷ is ortho-OCOC₁₋₃-alkyl or meta- orpara-CH₂N(R⁸)₂, where R⁸ is C₁₋₄-alkyl or 4-morpholino, or R⁴ representsmeta-S—C₁₋₃-alkyl, meta-Cl, meta-F, meta-CR⁹R¹⁰R¹¹, ortho-OH,ortho-O—C₂₋₃-alkyl, para-F or para-CR⁹R¹⁰R¹¹, where R⁹, R¹⁰ and R¹¹independently represent H or F, or R⁵ represents para-Cl, para-F,para-OH or para-O—C₁₋₃-alkyl, and R⁴ represents meta-Cl, meta-F, meta-OHor meta-O—C₁₋₃-alkyl, or R⁴ and R⁵ together represent 3,4-OCH═CH— or3,4-OCH═CHO—; or a salt thereof with a physiologically acceptable acid.7. An analgesic composition comprising at least one1-phenyl-3-dimethylaminopropane diastereoisomer having a configurationcorresponding to formula Ia′:

wherein X represents OH, F, Cl, H or an OCOR⁶ group in which R⁶ is aC₁₋₃-alkyl group; R¹ is a C₁₋₄-alkyl group; R² represents H or aC₁₋₄-alkyl group, and R³ is different from R² and represents H or astraight chain C₁₋₄-alkyl group, and R⁵ represents H, and R⁴ representsmeta-O—Z, where Z is H, C₁₋₃-alkyl, PO(OC₁₋₄alkyl)₂, CO(OC₁₋₅-alkyl),CONH—C₆H₄—(C₁₋₃-alkyl) or CO—C₆H₄—R⁷, in which R⁷ is ortho-OCOC₁₋₃-alkylor meta- or para-CH₂N(R⁸)₂, where R⁸ is C₁₋₄-alkyl or 4-morpholino, orR⁴ represents meta-S—C₂₋₃-alkyl, meta-Cl, meta-F, meta-CR⁹R¹⁰R¹¹,ortho-OH, ortho-O—C₂₋₃-alkyl, para-F or para-CR⁹R¹⁰R¹¹, where R⁹, R¹⁰and R¹¹ independently represent H or F, or R⁵ represents para-Cl,para-F, para-OH or para-O—C₁₋₃-alkyl, and R⁴ represents meta-Cl, meta-F,meta-OH or meta-O—C₁₋₃-alkyl, or R⁴ and R⁵ together represent3,4-OCH═CH— or 3,4-OCH═CHO—; or a salt thereof with a physiologicallyacceptable acid, and at least one conventional pharmaceutical carrier oradjuvant.
 8. A method of treating a mammal suffering from pain, saidmethod comprising administering to said mammal an effective analgesicamount of a 1-phenyl-3-dimethylaminopropane compound corresponding toformula I

wherein X represents OH, F, Cl, H or an OCOR⁶ group in which R⁶ is aC₁₋₃-alkyl group; R¹ is a C₁₋₄-alkyl group; R² represents H or aC₁₋₄-alkyl group and R³ represents H or a straight chain C₁₋₄-alkylgroup, or R² and R³ together form a C₄₋₇ cycloalkyl radical, and R⁵represents H, and R⁴ represents meta-O—Z, where Z is H, C₁₋₃-alkyl,PO(OC₁₋₄alkyl)₂, CO(OC₁₋₅-alkyl), CONH—C₆H₄—(C₁₋₃-alkyl) or CO—C₆H₄—R⁷,in which R⁷ is ortho-OCOC₁₋₃-alkyl or meta- or para-CH₂N(R⁸)₂, where R⁸is C₁₋₄-alkyl or 4-morpholino, or R⁴ represents meta-S—C₁₋₃-alkyl,meta-Cl, meta-F, meta-CR⁹R¹⁰R¹¹, ortho-OH, ortho-O—C₂₋₃₋alkyl, para-F orpara-CR⁹R¹⁰R¹¹, where R⁹, R¹⁰ and R¹¹ independently represent H or F, orR⁵ represents para-Cl, para-F, para-OH or para-O—C₁₋₃-alkyl, and R⁴represents meta-Cl, meta-F, meta-OH or meta-O—C₁₋₃-alkyl, or R⁴ and R⁵together represent 3,4-OCH═CH— or 3,4-OCH═CHO—, or a salt thereof with aphysiologically acceptable acid.
 9. An isolated 1-phenyl- 3-dimethylaminopropane diastereoisomer having a configurationcorresponding to at least one of formulae Ia′ and Ic′;

wherein X represents OH, F, Cl, H or an OCOR ⁶ group in which R ⁶ is a C₁₋₃-alkyl group, R ¹ is a C ₁₋₄-alkyl group, R ² represents a C_(n)-alkyl group, wherein n=1-4, R ³ is different from R ² andrepresents H or a straight chain C _(m)-alkyl group, wherein 0<m<n, andR ⁵ represents H, and R ⁴ represents meta-O—Z, where Z is H, C₁₋₃-alkyl, PO(OC ₁₄-alkyl)₂ , CO(OC ₁₋₅-alkyl), CONH—C ₆ H ₄—(C₁₋₃-alkyl) or CO—C ₆ H ₄ —R ⁷ , in which R ⁷ is ortho-OCOC ₁₋₃-alkyl ormeta- or para-CH ₂ N(R ⁸)₂ , where R ⁸ is C ₁₋₄-alkyl or 4 -morpholino,or R ⁴ represents meta-S—C ₁₋₃-alkyl, meta-Cl, meta-F, meta-CR ⁹ R ¹⁰ R¹¹ , ortho-OH, ortho-O—C ₂₋₃-alkyl, para-F or para-CR ⁹ R ¹⁰ R ¹¹ ,where R ⁹ , R ¹⁰ and R ¹¹ independently represent H or F, or R ⁵represents para-Cl, para-F, para-OH or para-O—C ₁₋₃-alkyl, and R ⁴represents meta-Cl, meta-F, meta-OH or meta-O—C ₁₋₃-alkyl, or R ⁴ and R⁵ together represent 3,4 -OCH═CH— or 3,4 -OCH═CHO—, or a salt thereofwith a physiologically acceptable acid.
 10. An isolated 1-phenyl- 3-dimethylaminopropane diastereoisomer having a configurationcorresponding to formula Ia′:

wherein X represents OH, F, Cl, H or an OCOR ⁶ group in which R ⁶ is a C₁₋₃-alkyl group, R ¹ is a C ₁₋₄-alkyl group, R ² represents a C₁₋₄-alkyl group, and R ³ is different from R ² and represents H or astraight chain C ₁₋₃-alkyl group, such that X and the dimethylaminogroup are disposed threo in relation to each other, and R ⁵ representsH, and R ⁴ represents meta-O—Z, where Z is H, C ₁₋₃-alkyl, PO(OC₁₄-alkyl)₂ , CO(OC ₁₋₅-alkyl), CONH—C ₆ H ₄—(C ₁₋₃-alkyl) or CO—C ₆ H ₄—R ⁷ , in which R ⁷ is ortho-OCOC ₁₋₃-alkyl or meta- or para-CH ₂ N(R⁸)₂ , where R ⁸ is C ₁₋₄-alkyl or 4 -morpholino, or R ⁴ representsmeta-S—C ₁₋₃-alkyl, meta-Cl, meta-F, meta-CR ⁹ R ¹⁰ R ¹¹ , ortho-OH,ortho-O—C ₂₋₃-alkyl, para-F or para-CR ⁹ R ¹⁰ R ¹¹ , where R ⁹ , R ¹⁰and R ¹¹ independently represent H or F, or R ⁵ represents para-Cl,para-F, para-OH or para-O—C ₁₋₃-alkyl, and R ⁴ represents meta-Cl,meta-F, meta-OH or meta-O—C ₁₋₃-alkyl, or R ⁴ and R ⁵ together represent3,4 -OCH═CH— or 3,4 -OCH═CHO—, or a salt thereof with a physiologicallyacceptable acid.
 11. An isolated 1-phenyl- 3 -dimethylaminopropanediastereoisomer according to claim 10 , wherein R ⁵ is H, and R ⁴ ismeta-OCH ₃ .
 12. An isolated 1-phenyl- 3 -dimethylaminopropanediastereoisomer according to claim 10 , wherein R ⁵ is H, and R ⁴ ismeta-OH.
 13. An isolated 1-phenyl- 3 -dimethylaminopropanediastereoisomer according to claim 10 , wherein X represents OH, F, Cl,or H; R ¹ is a C ₁₋₄-alkyl group; R ² represents CH ₃ ; R ³ is H; and R⁵ represents H, and R ⁴ represents meta-O—C ₁₋₃-alkyl, meta-OH, meta-S—C₁₋₃-alkyl, meta-F, meta-Cl, meta-CH ₃ , meta-CF ₂ H, meta-CF ₃ , orpara-CF ₃ , or R ⁵ represents para-Cl, or para-F, and R ⁴ representsmeta-Cl, or meta-F, or R ⁴ and R ⁵ together represent 3,4 -OCH═CH—. 14.An isolated 1-phenyl- 3 -dimethylaminopropane diastereoisomer accordingto claim 10 , wherein X represents OH, F, Cl, or an OCOR ⁶ group inwhich R ⁶ is a C ₁₋₃-alkyl group.
 15. An isolated 1-phenyl- 3-dimethylaminopropane diastereoisomer according to claim 10 , wherein R² is CH ₃ , and R ³ is H.
 16. An isolated 1-phenyl- 3-dimethylaminopropane diastereoisomer according to claim 10 , wherein R⁹ , R ¹⁰ and R ¹¹ represent F.
 17. An isolated 1-phenyl- 3-dimethylaminopropane diastereoisomer according to claim 10 , wherein Xrepresents OH.
 18. An isolated 1-phenyl- 3 -dimethylaminopropanediastereoisomer according to claim 10 , wherein X represents F, Cl, H oran OCOR ⁶ group in which R ⁶ is a C ₁₋₃-alkyl group.
 19. An isolated1-phenyl- 3 -dimethylaminopropane diastereoisomer according to claim 6 ,wherein R ⁵ is H and R ⁴ is meta-OCH ₃ .
 20. An isolated 1-phenyl- 3-dimethylaminopropane diastereoisomer according to claim 6 , wherein R ⁵is H and R ⁴ is meta-OH.
 21. An isolated 1-phenyl- 3-dimethylaminopropane diastereoisomer according to claim 6 , wherein Xrepresents OH, F, Cl, or an OCOR ⁶ group in which R ⁶ is a C ₁₋₃-alkylgroup.
 22. An isolated 1-phenyl- 3 -dimethylaminopropane diastereoisomeraccording to claim 6 , wherein R ⁹ , R ¹⁰ and R ¹¹ represent F.
 23. Anisolated 1-phenyl- 3 -dimethylaminopropane diastereoisomer according toclaim 6 , wherein X represents OH.
 24. An isolated 1-phenyl- 3-dimethylaminopropane diastereoisomer according to claim 6 , wherein Xrepresents F, Cl, H or an OCOR ⁶ group in which R ⁶ is a C ₁₋₃-alkylgroup.
 25. An isolated 1-phenyl- 3 -dimethylaminopropane diastereoisomerhaving a configuration corresponding to at least one of formulae Ia′ andIc′:

wherein X represents OH, F, Cl, H or an OCOR ⁶ group in which R ⁶ is a C₁₋₃-alkyl group, R ¹ is a C ₁₋₄-alkyl group, R ² represents a C₁₋₄-alkyl group, and R ³ is different from R ² and represents H or astraight chain C ₁₋₃-alkyl group, such that X and the dimethylaminogroup are disposed threo in relation to each other, and R ⁵ representsH, and R ⁴ represents meta-O—Z, where Z is H, C ₁₋₃-alkyl, PO(OC₁₄-alkyl)₂ , CO(OC ₁₋₅-alkyl), CONH—C ₆ H ₄—(C ₁₋₃-alkyl) or CO—C ₆ H ₄—R ⁷ , in which R ⁷ is ortho-OCOC ₁₋₃-alkyl or meta- or para-CH ₂ N(R⁸)₂ , where R ⁸ is C ₁₋₄-alkyl or 4 -morpholino, or R ⁴ representsmeta-S—C ₁₋₃-alkyl, meta-Cl, meta-F, meta-CR ⁹ R ¹⁰ R ¹¹ , ortho-OH,ortho-O—C ₂₋₃-alkyl, para-F or para-CR ⁹ R ¹⁰ R ¹¹ , where R ⁹ , R ¹⁰and R ¹¹ independently represent H or F, or R ⁵ represents para-Cl,para-F, para-OH or para-O—C ₁₋₃-alkyl, and R ⁴ represents meta-Cl,meta-F, meta-OH or meta-O—C ₁₋₃-alkyl, or R ⁴ and R ⁵ together represent3,4 -OCH═CH— or 3,4 -OCH═CHO—, or a salt thereof with a physiologicallyacceptable acid.
 26. An isolated 1-phenyl- 3 -dimethylaminopropanediastereoisomer according to claim 25 , wherein X represents OH, F, Cl,or H; R ¹ is a C ₁₋₄-alkyl group; R ² represents CH ₃ ; R ³ is H; and R⁵ represents H, and R ⁴ represents meta-OC ₁₋₃-alkyl, meta-OH, meta-S—C₁₋₃-alkyl, meta-F, meta-Cl, meta-CH ₃ , meta-CF ₂ H, meta-CF ₃ , orpara-CF ₃ , or R ⁵ represents para-Cl, or para-F, and R ⁴ representsmeta-Cl, or meta-F, or R ⁴ and R ⁵ together represent 3,4 -OCH═CH—. 27.An isolated 1-phenyl- 3 -dimethylaminopropane diastereoisomer accordingto claim 25 , wherein R ⁵ is H and R ⁴ is meta-OCH ₃ .
 28. An isolated1-phenyl- 3 -dimethylaminopropane diastereoisomer according to claim 25, wherein R ⁵ is H and R ⁴ is meta-OH.
 29. An isolated 1-phenyl- 3-dimethylaminopropane diastereoisomer according to claim 25 , wherein Xrepresents OH, F, Cl or an OCOR ⁶ group in which R ⁶ is a C ₁₋₃-alkylgroup.
 30. An isolated 1-phenyl- 3 -dimethylaminopropane diastereoisomeraccording to claim 25 , wherein R ² is CH ₃ , and R ³ is H.
 31. Anisolated 1-phenyl- 3 -dimethylaminopropane diastereoisomer according toclaim 25 , wherein R ⁹ , R ¹⁰ and R ¹¹ represent F.
 32. An isolated1-phenyl- 3 -dimethylaminopropane diastereoisomer according to claim 25, wherein X represents OH.
 33. An isolated 1-phenyl- 3-dimethylaminopropane diastereoisomer according to claim 25 , wherein Xrepresents F, Cl, H or an OCOR ⁶ group in which R ⁶ is a C ₁₋₃-alkylgroup.
 34. An isolated 1-phenyl- 3 -dimethylaminopropane diastereoisomerhaving a configuration corresponding to at least one of formulae Ia andIc:

wherein X represents OH, F, Cl, H or an OCOR ⁶ group in which R ⁶ is a C₁₋₃-alkyl group; R ¹ is a C ₁₋₄-alkyl group; R ² represents a C₁₋₄-alkyl group, and R ⁵ represents H, and R ⁴ represents meta-O—Z,where Z is H, C ₁₋₃-alkyl, PO(OC ₁₄-alkyl)₂ , CO(OC ₁₋₅-alkyl), CONH—C ₆H ₄—(C ₁₋₃-alkyl) or CO—C ₆ H ₄ —R ⁷ , in which R ⁷ is ortho-OCOC₁₋₃-alkyl or meta- or para-CH ₂ N(R ⁸)₂ , where R ⁸ is C ₁₋₄-alkyl or 4-morpholino, or R ⁴ represents meta-S—C ₁₋₃-alkyl, meta-Cl, meta-F,meta-CR ⁹ R ¹⁰ R ¹¹ , ortho-OH, ortho-O—C ₂₋₃-alkyl, para-F or para-CR ⁹R ¹⁰ R ¹¹ , where R ⁹ , R ¹⁰ and R ¹¹ independently represent H or F, orR ⁵ represents para-Cl, para-F, para-OH or para-O—C ₁₋₃-alkyl, and R ⁴represents meta-Cl, meta-F, meta-OH or meta-O—C ₁₋₃-alkyl, or R ⁴ and R⁵ together represent 3,4 -OCH═CH— or 3,4 -OCH═CHO—; or a salt thereofwith a physiologically acceptable acid.
 35. An isolated 1-phenyl- 3-dimethylaminopropane diastereoisomer according to claim 34 , wherein R⁵ is H and R ⁴ is meta-OCH ₃ .
 36. An isolated 1-phenyl- 3-dimethylaminopropane diastereoisomer according to claim 34 , wherein R⁵ is H and R ⁴ is meta-OH.
 37. An isolated 1-phenyl- 3-dimethylaminopropane diastereoisomer according to claim 34 , wherein Xrepresents OH, F, Cl or an OCOR ⁶ group in which R ⁶ is a C ₁₋₃-alkylgroup.
 38. An isolated 1-phenyl- 3 -dimethylaminopropane diastereoisomeraccording to claim 34 , wherein R ⁹ , R ¹⁰ and R ¹¹ represent F.
 39. Anisolated 1-phenyl- 3 -dimethylaminopropane diastereoisomer according toclaim 34 , wherein X represents OH.
 40. An isolated 1-phenyl- 3-dimethylaminopropane diastereoisomer according to claim 34 , wherein Xrepresents F, Cl, H or an OCOR ⁶ group in which R ⁶ is a C ₁₋₃-alkylgroup.
 41. An isolated 1-phenyl- 3 -dimethylaminopropane diastereoisomerhaving a configuration corresponding to formula Ic′:

wherein X represents OH, F, Cl, H or an OCOR ⁶ group in which R ⁶ is a C₁₋₃-alkyl group, R ¹ is a C ₁₋₄-alkyl group, R ² represents a C₁₋₄-alkyl group, and R ³ is different from R ² and represents H or astraight chain C ₁₋₃-alkyl group, such that X and the dimethylaminogroup are disposed threo in relation to each other, and R ⁵ representsH, and R ⁴ represents meta-O—Z, where Z is H, C ₁₋₃-alkyl, PO(OC₁₄-alkyl)₂ , CO(OC ₁₋₅-alkyl), CONH—C ₆ H ₄—(C ₁₋₃-alkyl) or CO—C ₆ H ₄—R ⁷ , in which R ⁷ is ortho-OCOC ₁₋₃-alkyl or meta- or para-CH ₂ N(R⁸)₂ , where R ⁸ is C ₁₋₄-alkyl or 4 -morpholino, or R ⁴ representsmeta-S—C ₁₋₃-alkyl, meta-Cl, meta-F, meta-CR ⁹ R ¹⁰ R ¹¹ , ortho-OH,ortho-O—C ₂₋₃-alkyl, para-F or para-CR ⁹ R ¹⁰ R ¹¹ , where R ⁹ , R ¹⁰and R ¹¹ independently represent H or F, or R ⁵ represents para-Cl,para-F, para-OH or para-O—C ₁₋₃-alkyl, and R ⁴ represents meta-Cl,meta-F, meta-OH or meta-O—C ₁₋₃-alkyl, or R ⁴ and R ⁵ together represent3,4 -OCH═CH— or 3,4 -OCH═CHO—, or a salt thereof with a physiologicallyacceptable acid.
 42. An isolated 1-phenyl- 3 -dimethylaminopropanediastereoisomer according to claim 41 , wherein X represents OH, F, Cl,or H; R ¹ is a C ₁₋₄-alkyl group; R ² represents CH ₃ ; R ⁸ is H; and R⁵ represents H, and R ⁴ represents meta-OC ₁₋₃-alkyl, meta-OH, meta-S—C₁₋₃-alkyl, meta-F, meta-Cl, meta-CH ₃ , meta-CF ₂ H, meta-CF ₃ , orpara-CF ₃ , or R ⁵ represents para-Cl, or para-F, and R ⁴ representsmeta-Cl, or meta-F, or R ⁴ and R ⁵ together represent 3,4 -OCH═CH—. 43.An isolated 1-phenyl- 3 -dimethylaminopropane diastereoisomer accordingto claim 41 , wherein R ⁵ is H and R ⁴ is meta-OCH ₃ .
 44. An isolated1-phenyl- 3 -dimethylaminopropane diastereoisomer according to claim 41, wherein R ⁵ is H and R ⁴ is meta-OH.
 45. An isolated 1-phenyl- 3-dimethylaminopropane diastereoisomer according to claim 41 , wherein Xrepresents OH, F, Cl or an OCOR ⁶ group in which R ⁶ is a C ₁₋₃-alkylgroup.
 46. An isolated 1-phenyl- 3 -dimethylaminopropane diastereoisomeraccording to claim 41 , wherein R ² is CH ₃ , and R ³ is H.
 47. Anisolated 1-phenyl- 3 -dimethylaminopropane diastereoisomer according toclaim 41 , wherein R ⁹ , R ¹⁰ and R ¹¹ represent F.
 48. An isolated1-phenyl- 3 -dimethylaminopropane diastereoisomer according to claim 41, wherein X represents OH.
 49. An isolated 1-phenyl- 3-dimethylaminopropane diastereoisomer according to claim 41 , wherein Xrepresents F, Cl, H or an OCOR ⁶ group in which R ⁶ is a C ₁₋₃-alkylgroup.
 50. An isolated 1-phenyl- 3 -dimethylaminopropane diastereoisomerhaving a configuration corresponding to formula Ic:

wherein X represents OH, F, Cl, H or an OCOR ⁶ group in which R ⁶ is a C₁₋₃-alkyl group; R ¹ is a C ₁₋₄-alkyl group; R ² represents a C₁₋₄-alkyl group, and R ⁵ represents H, and R ⁴ represents meta-O—Z,where Z is H, C ₁₋₃-alkyl, PO(OC ₁₋₄-alkyl)₂ , CO(OC ₁₋₅-alkyl), CONH—C₆ H ₄—(C ₁₋₃-alkyl) or CO—C ₆ H ₄ —R ⁷ , in which R ⁷ is ortho-OCOC₁₋₃-alkyl or meta- or para-CH ₂ N(R ⁸)₂ , where R ⁸ is C ₁₋₄-alkyl or 4-morpholino, or R ⁴ represents meta-S—C ₁₋₃-alkyl, meta-Cl, meta-F,meta-CR ⁹ R ¹⁰ R ¹¹ , ortho-OH, ortho-O—C ₂₋₃-alkyl, para-F or para-CR ⁹R ¹⁰ R ¹¹ , where R ⁹ , R ¹⁰ and R ¹¹ independently represent H or F, orR ⁵ represents para-Cl, para-F, para-OH or para-O—C ₁₋₃-alkyl, and R ⁴represents meta-Cl, meta-F, meta-OH or meta-O—C ₁₋₃-alkyl, or R ⁴ and R⁵ together represent 3,4 -OCH═CH— or 3,4 -OCH═CHO—; or a salt thereofwith a physiologically acceptable acid.
 51. An isolated 1-phenyl- 3-dimethylaminopropane diastereoisomer according to claim 50 , wherein R⁵ is H and R ⁴ is meta-OCH ₃ .
 52. An isolated 1-phenyl- 3-dimethylaminopropane diastereoisomer according to claim 50 , wherein R⁵ is H and R ⁴ is meta-OH.
 53. An isolated 1-phenyl- 3-dimethylaminopropane diastereoisomer according to claim 50 , wherein Xrepresents OH, F, Cl or an OCOR ⁶ group in which R ⁶ is a C ₁₋₃-alkylgroup.
 54. An isolated 1-phenyl- 3 -dimethylaminopropane diastereoisomeraccording to claim 50 , wherein R ⁹ , R ¹⁰ and R ¹¹ represent F.
 55. Anisolated 1-phenyl- 3 -dimethylaminopropane diastereoisomer according toclaim 50 , wherein X represents OH.
 56. An isolated 1-phenyl- 3-dimethylaminopropane diastereoisomer according to claim 50 , wherein Xrepresents F, Cl, H or an OCOR ⁶ group in which R ⁶ is a C ₁₋₃-alkylgroup.
 57. An isolated 1-phenyl- 3 -dimethylaminopropane diastereoisomeraccording to claim 34 , wherein the compound is ( 2S, 3S)- 1-dimethylamino- 3 -( 3 -methoxyphenyl)- 2 -methylpentan- 3 -olhydrochloride (− 1 ).
 58. An isolated 1-phenyl- 3 -dimethylaminopropanediastereoisomer according to claim 34 , wherein the compound is (+)-(2R, 3R)- 1 -dimethylamino- 3 -( 3 -methoxyphenyl)- 2 -methylpentan- 3-ol hydrochloride (+ 1 ).
 59. An isolated 1-phenyl- 3-dimethylaminopropane diastereoisomer according to claim 34 , whereinthe compound is (+)-( 2R, 3R)- 1 -dimethylamino- 3 -( 3 -methoxyphenyl)-2 -methylpentan- 3 -ol hydrochloride (+ 1 ).
 60. An isolated 1-phenyl- 3-dimethylaminopropane diastereoisomer according to claim 34 , whereinthe compound is (+)-( 1S,2S)- 3 -( 3 -dimethylamino- 1 -ethyl- 2-methylpropyl)-phenol hydrochloride (+ 21 ).
 61. (−)-( 1R,2R)- 3 -( 3-dimethylamino- 1 -ethyl- 2 -methylpropyl)-phenol hydrochloride (− 21 ).62. An isolated 1-phenyl- 3 -dimethylaminopropane diastereoisomeraccording to claim 34 , wherein the compound is (+)-( 1RS,2RS)- 3 -( 3-dimethylamino- 1 -ethyl- 2 -methylpropyl)-phenol hydrochloride (+ 21 ).63. An isolated 1-phenyl- 3 -dimethylaminopropane diastereoisomeraccording to claim 34 , wherein the compound is (+)-( 2S,3S)-[ 3 -( 3-methoxyphenyl)- 2 -methylpentyl]-dimethylamine hydrochloride (+ 23 ).64. An isolated 1-phenyl- 3 -dimethylaminopropane diastereoisomeraccording to claim 34 , wherein the compound is (−)-( 2R,3R)-[ 3 -( 3-methoxyphenyl)- 2 -methylpentyl]-dimethylamine hydrochloride (− 23 ).65. An isolated 1-phenyl- 3 -dimethylaminopropane diastereoisomeraccording to claim 34 , wherein the compound is (+)-( 2RS, 3RS)-[3 -( 3-methoxyphenyl)- 2 -methylpentyl]-dimethylamine hydrochloride (+23). 66.An analgesic composition comprising at least one 1-phenyl- 3-dimethylaminopropane diastereoisomer having a configurationcorresponding to at least one of formulae Ia′ and Ic′:

wherein X represents OH, F, Cl, H or an OCOR ⁶ group in which R ⁶ is a C₁₋₃-alkyl group; R ¹ is a C ₁₋₄-alkyl group; R ² represents a C₁₋₄-alkyl group, and R ³ is different from R ² and represents H or astraight chain C ₁₋₃-alkyl group, such that X and the dimethylaminogroup are disposed threo in relation to each other, and R ⁵ representsH, and R ⁴ represents meta-O—Z, C ₆ H ₄—(C ₁₋₃-alkyl) or CO—C ₆ H ₄ —R ⁷, in which R ⁷ is ortho-OCOC ₁₋₃-alkyl or meta- or para-CH ₂ N(R ⁸)₂ ,where R ⁸ is C ₁₋₄-alkyl or 4 -morpholino, or R ⁴ represents meta-S—C₁₋₃-alkyl, meta-Cl, meta-F, meta-CR ⁹ R ¹⁰ R ¹¹ , ortho-OH, ortho-O—C₂₋₃-alkyl, para-F or para-CR ⁹ R ¹⁰ R ¹¹ , where R ⁹ , R ¹⁰ and R ¹¹independently represent H or F, or R ⁵ represents para-Cl, para-F,para-OH or para-O—C ₁₋₃-alkyl, and R ⁴ represents meta-Cl, meta-F,meta-OH or meta-O—C ₁₋₃-alkyl, or R ⁴ and R ⁵ together represent 3,4-OCH═CH— or 3,4 -OCH═CHO—; or a salt thereof with a physiologicallyacceptable acid, and at least one suitable pharmaceutical carrier oradjuvant.
 67. An analgesic composition according to claim 66, wherein Xrepresents OH, F, Cl, or H; R ¹ represents a C ₁₋₄-alkyl group; R ²represents CH ₃ ; R ³ is H; and R ⁵ represents H, and R ⁴ representsmeta-OC ₁₋₃-alkyl, meta-OH, meta-S—C ₁₋₃-alkyl, meta-F, meta-Cl, meta-CH₃ , meta-CF ₂ H, meta-CF ₃ , or R ⁵ represents para-Cl, or para-F, and R⁴ represents meta-Cl, or meta-F, or R ⁴ and R ⁵ together represent 3,4-OCH═CH—.
 68. An analgesic composition according to claim 66, wherein R⁵is H and R ⁴ is meta-OCH ₃ .
 69. An analgesic composition according toclaim 66, wherein R⁵ is H and R ⁴ is meta-OH.
 70. An analgesiccomposition according to claim 66, wherein X represents OH, F, Cl or anOCOR⁶ group in which R ⁶ is a C ₁₋₃-alkyl group.
 71. An analgesiccomposition according to claim 66, wherein R² is CH ₂ , and R ³ is H.72. An analgesic composition according to claim 66, wherein R⁹ , R ¹⁰and R ¹¹ represent F.
 73. An analgesic composition according to claim66, wherein X represents OH.
 74. An analgesic composition according toclaim 66, wherein X represents F, Cl, H or an OCOR⁶ group in which R ⁶is a C ₁₋₃-alkyl group.
 75. An analgesic composition according to claim66, wherein the 1-phenyl- 3 -dimethylaminopropane diastereoisomer has aconfiguration corresponding to formula Ia′.
 76. An analgesic compositionaccording to claim 66, wherein the 1-phenyl- 3 -dimethylaminopropanediastereoisomer has a configuration corresponding to formula Ic′.
 77. Ananalgesic composition comprising at least one 1-phenyl- 3-dimethylaminopropane diastereoisomer having a configurationcorresponding to at least one of formulae Ia and Ic:

wherein X represents OH, F, Cl, H or an OCOR ⁶ group in which R ⁶ is a C₁₋₃-alkyl group; R ¹ is a C ₁₋₄-alkyl group; R ² represents a C₁₋₄-alkyl group, and R ⁵ represents H, and R ⁴ represents meta-O—Z,where Z is H, C ₁₋₃-alkyl, PO(OC ₁₋₄-alkyl)₂ , CO(OC₁₋₅-alkyl), CONH—C ₆H ₄—(C ₁₋₃-alkyl) or CO—C ₆ H ₄ —R ⁷ , in which R ⁷ is ortho-OCOC₁₋₃-alkyl or meta- or para-CH ₂ N(R ⁸)₂ , where R ⁸ is C ₁₋₄-alkyl or 4-morpholino, or R ⁴ represents meta-S—C ₁₋₃-alkyl, meta-Cl, meta-F,meta-CR ⁹ R ¹⁰ R ¹¹ , ortho-OH, ortho-O—C ₂₋₃-alkyl, para-F or para-CR ⁹R ¹⁰ R ¹¹ , where R ⁹ , R ¹⁰ and R ¹¹ independently represent H or F, orR ⁵ represents para-Cl, para-F, para-OH or para-O—C ₁₋₃-alkyl, and R ⁴represents meta-Cl, meta-F, meta-OH or meta-O—C ₁₋₃-alkyl, or R ⁴ and R⁵ together represent 3,4 -OCH═CH— or 3,4 -OCH═CHO—; or a salt thereofwith a physiologically acceptable acid, and at least one suitablepharmaceutical carrier or adjuvant.
 78. An analgesic compositionaccording to claim 77, wherein R⁵ is H and R ⁴ is meta-OCH ₃ .
 79. Ananalgesic composition according to claim 77, wherein R⁵ is H and R ⁴ ismeta-OH.
 80. An analgesic composition according to claim 77, wherein Xrepresents OH, F, Cl or an OCOR⁶ group in which R ⁶ is a C ₁₋₃-alkylgroup.
 81. An analgesic composition according to claim 77, wherein R⁹ ,R ¹⁰ and R ¹¹ represent F.
 82. An analgesic composition according toclaim 77, wherein X represents OH.
 83. An analgesic compositionaccording to claim 77, wherein X represents F, Cl, H or an OCOR⁶ groupin which R ⁶ is a C ₁₋₃-alkyl group.
 84. An analgesic compositionaccording to claim 77, wherein the 1-phenyl- 3 -dimethylaminopropanediastereoisomer has a configuration corresponding to formula Ia.
 85. Ananalgesic composition according to claim 77, wherein the 1-phenyl- 3-dimethylaminopropane diastereoisomer has a configuration correspondingto formula Ic.
 86. A method according to claim 8, wherein X representsOH, F, Cl, or H; R ¹ represents a C ₁₋₄-alkyl group; R ² represents CH ₈; R ³ represents H, and R ⁵ represents H, and R ⁴ represents meta-OC₁₋₈-alkyl, meta-OH, meta-S—C ₁₋₃-alkyl, meta-F, meta-Cl, meta-CH ₃ ,meta-CF ₂ H, meta-CF ₃ , or para-CF ₃ , or R ⁵ represents para-Cl, orpara-F, and R ⁴ represents meta-Cl, or meta-F, or R ⁴ and R ⁵ togetherrepresent 3,4 -OCH═CH—.
 87. A method according to claim 8, wherein R⁵ isH and R ⁴ is meta-OCH ₈ .
 88. An method according to claim 8, wherein R⁵is H and R ⁴ is meta-OH.
 89. A method according to claim 8, wherein Xrepresents OH, F, Cl or an OCOR⁶ group in which R ⁶ is a C ₁₋₃-alkylgroup.
 90. A method according to claim 8, wherein R² is C ₁₋₄-alkyl, andR ³ is different from R ² and is H or C ₁₋₃ alkyl.
 91. A methodaccording to claim 8, wherein R⁹ , R ¹⁰ and R ¹¹ represent F.
 92. Amethod according to claim 8, wherein X represents OH.
 93. A methodaccording to claim 8, wherein X represents F, Cl, H or an OCOR⁶ group inwhich R ⁶ is a C ₁₋₃-alkyl group.
 94. A method according to claim 8,wherein X represents H.
 95. A method according to claim 8, wherein thecompound of formula I has a configuration corresponding to at least oneof formulae Ia′ and Ic′:

wherein X represents OH, F, Cl, H or an OCOR ⁶ group in which R ⁶ is a C₁₋₃-alkyl group, R ¹ is a C ₁₋₄-alkyl group, R ² represents a C₁₋₄-alkyl group, and R ³ is different from R ² and represents H or astraight chain C ₁₋₃-alkyl group, such that X and the dimethylaminogroup are disposed threo in relation to each other, and R ⁵ representsH, and R ⁴ represents meta-O—Z, where Z is H, C ₁₋₃-alkyl, PO(OC₁₄-alkyl)₂ , CO(OC ₁₋₅-alkyl), CONH—C ₆ H ₄—(C ₁₋₃-alkyl) or CO—C ₆ H ₄—R ⁷ , in which R ⁷ is ortho-OCOC ₁₋₃-alkyl or meta- or para-CH ₂ N(R⁸)₂ , where R ⁸ is C ₁₋₄-alkyl or 4 -morpholino, or R ⁴ representsmeta-S—C ₁₋₃-alkyl, meta-Cl, meta-F, meta-CR ⁹ R ¹⁰ R ¹¹ , ortho-OH,ortho-O—C ₂₋₃-alkyl, para-F or para-CR ⁹ R ¹⁰ R ¹¹ , where R ⁹ , R ¹⁰and R ¹¹ independently represent H or F, or R ⁵ represents para-Cl,para-F, para-OH or para-O—C ₁₋₃-alkyl, and R ⁴ represents meta-Cl,meta-F, meta-OH or meta-O—C ₁₋₃-alkyl, or R ⁴ and R ⁵ together represent3,4 -OCH═CH— or 3,4 -OCH═CHO—, or a salt thereof with a physiologicallyacceptable acid.
 96. A method according to claim 95, wherein Xrepresents OH, F, Cl, or H; R ¹ represents a C ₁₋₄-alkyl group; R ²represents CH ₃ ; R ³ represents H, and R ⁵ represents H, and R ⁴represents meta-OC ₁₋₃-alkyl, meta-OH, meta-S—C ₁₋₃-alkyl, meta-F,meta-Cl, meta-CH ₃ , meta-CF ₂ H, meta-CF ₃ , or para-CF ₃ , or R ⁵represents para-Cl, or para-F, and R ⁴ represents meta-Cl, or meta-F, orR ⁴ and R ⁵ together represent 3,4 -OCH═CH—.
 97. A method according toclaim 95, wherein R⁵ is H and R ⁴ is meta-OCH ₃ .
 98. An methodaccording to claim 95, wherein R⁵ is H and R ⁴ is meta-OH.
 99. A methodaccording to claim 95, wherein X represents OH, F, Cl or an OCOR⁶ groupin which R ⁶ is a C ₁₋₃-alkyl group.
 100. A method according to claim95, wherein R² is CH ₃ , and R ³ is H.
 101. A method according to claim95, wherein R⁹ , R ¹⁰ and R ¹¹ represent F.
 102. A method according toclaim 95, wherein X represents OH.
 103. A method according to claim 95,wherein X represents F, Cl, H or an OCOR⁶ group in which R ⁶ is a C₁₋₃-alkyl group.
 104. A method according to claim 95, wherein the1-phenyl- 3 -dimethylaminopropane diastereoisomer has a configurationcorresponding to formula Ia′.
 105. A method according to claim 95,wherein the 1-phenyl- 3 -dimethylaminopropane diastereoisomer has aconfiguration corresponding to formula Ic′.
 106. A method according toclaim 8, wherein the compound of formula I has a configurationcorresponding to at least one of formulae Ia and Ic:

wherein X represents OH, F, Cl, H or an OCOR ⁶ group in which R ⁶ is a C₁₋₃-alkyl group; R ¹ is a C ₁₋₄-alkyl group; R ² represents a C₁₋₄-alkyl group, and R ⁵ represents H, and R ⁴ represents meta-O—Z,where Z is H, C ₁₋₃-alkyl, PO(OC ₁₋₄-alkyl)₂ , CO(OC ₁₋₅-alkyl), CONH—C₆ H ₄—(C ₁₋₃-alkyl) or CO—C ₆ H ₄ —R ⁷ , in which R ⁷ is ortho-OCOC₁₋₃-alkyl or meta- or para-CH ₂ N(R ⁸)₂ , where R ⁸ is C ₁₋₄-alkyl or 4-morpholino, or R ⁴ represents meta-S—C ₁₋₃-alkyl, meta-Cl, meta-F,meta-CR ⁹ R ¹⁰ R ¹¹ , ortho-OH, ortho-O—C ₂₋₃-alkyl, para-F or para-CR ⁹R ¹⁰ R ¹¹ , where R ⁹ , R ¹⁰ and R ¹¹ independently represent H or F, orR ⁵ represents para-Cl, para-F, para-OH or para-O—C ₁₋₃-alkyl, and R ⁴represents meta-Cl, meta-F, meta-OH or meta-O—C ₁₋₃-alkyl, or R ⁴ and R⁵ together represent 3,4 -OCH═CH— or 3,4 -OCH═CHO—; or a salt thereofwith a physiologically acceptable acid.
 107. A method according to claim106, wherein X represents OH, F, Cl or an OCOR⁶ group in which R ⁶ is aC ₁₋₃-alkyl group.
 108. A method according to claim 106, wherein R⁹ , R¹⁰ and R ¹¹ represent F.
 109. A method according to claim 106, wherein Xrepresents OH.
 110. A method according to claim 106, wherein Xrepresents F, Cl, H or an OCOR⁶ group in which R ⁶ is a C ₁₋₃-alkylgroup.
 111. A method according to claim 106, wherein the compound is a1-phenyl- 3 -dimethylaminopropane diastereoisomer having a configurationcorresponding to formula Ia.
 112. A method according to claim 106,wherein the compound is a 1-phenyl- 3 -dimethylaminopropanediastereoisomer having a configuration corresponding to formula Ic. 113.A method according to claim 106, wherein R⁵ is H and R ⁴ is meta-OCH ₃ .114. A method according to claim 106, wherein R⁵ is H and R ⁴ ismeta-OH.
 115. A method according to claim 8, wherein the compound is(+)-( 1RS,2RS)- 3 -( 3 -dimethylamino- 1 -ethyl- 2 -methylpropyl)-phenolhydrochloride (+ 21 ).
 116. A method according to claim 8, wherein thecompound is (+)-( 1S,2S)- 3 -( 3 -dimethylamino- 1 -ethyl- 2-methylpropyl)-phenol hydrochloride (+ 21 ).
 117. A method according toclaim 8, wherein the compound is (−)-( 1R,2R)- 3 -( 3 -dimethylamino- 1-ethyl- 2 -methylpropyl)-phenol hydrochloride (− 21 ).
 118. A methodaccording to claim 8, wherein the compound is (+)-( 2RS,3RS)-[ 3 -( 3-methoxyphenyl)- 2 -methylpentyl]-dimethylamine hydrochloride (+23 ).119. A method according to claim 8, wherein the compound is (+)-(2S,3S)-[ 3 -( 3 -methoxyphenyl)- 2 -methylpentyl]-dimethylaminehydrochloride (+ 23 ).
 120. A method according to claim 8, wherein thecompound is (−)-( 2R,3R)-[ 3 -( 3 -methoxyphenyl)- 2-methylpentyl]-dimethylamine hydrochloride (− 23 ).
 121. A methodaccording to claim 8, wherein the compound is (+)-( 2RS, 3RS)- 1-dimethylamino- 3 -( 3 -methoxyphenyl)- 2 -methylpentan-3-olhydrochloride (+ 1 ).
 122. A method according to claim 8, wherein thecompound is (+)-( 2R, 3R)- 1 -dimethylamino- 3 -( 3 -methoxyphenyl)- 2-methylpentan-3-ol hydrochloride (+ 1 ).
 123. A method according toclaim 8, wherein the compound is (−)-( 2S, 3S)- 1 -dimethylamino- 3 -( 3-methoxyphenyl)- 2 -methylpentan-3-ol hydrochloride (− 1 ).
 124. Anisolated 1-phenyl- 3 -dimethylaminopropane diastereoisomer according toclaim 6 , wherein X is H.
 125. An isolated 1-phenyl- 3-dimethylaminopropane diastereoisomer according to claim 10 , wherein Xis H.
 126. An isolated 1-phenyl- 3 -dimethylaminopropane diastereoisomeraccording to claim 25 , wherein X is H.
 127. An isolated 1-phenyl- 3-dimethylaminopropane diastereoisomer according to claim 34 , wherein Xis H.
 128. An isolated 1-phenyl- 3 -dimethylaminopropane diastereoisomeraccording to claim 41 , wherein X is H.
 129. An isolated 1-phenyl- 3-dimethylaminopropane diastereoisomer according to claim 50 , wherein Xis H.
 130. An analgesic composition according to claim 66, wherein X isH.
 131. An analgesic composition according to claim 75, wherein X is H.132. An analgesic composition according to claim 76, wherein X is H.133. An analgesic composition according to claim 77, wherein X is H.134. An analgesic composition according to claim 84, wherein X is H.135. An analgesic composition according to claim 85, wherein X is H.136. A method according to claim 86, wherein X is H.
 137. A methodaccording to claim 95, wherein X is H.
 138. A method according to claim106, wherein X is H.
 139. A method according to claim 113, wherein X isH.
 140. A method according to claim 114, wherein X is H.
 141. Anisolated 1-phenyl- 3 -dimethylaminopropane diastereomer having aconfiguration corresponding to formula I:

wherein X represents H, R ¹ is a C ₁₋₄-alkyl group, R ² represents a C₁₋₄-alkyl group, R ³ is different from R ² and represents H or astraight chain C ₁₋₃-alkyl group, and R ⁵ represents H, and R ⁴represents meta-O—Z, where Z is H, C ₁₋₃-alkyl, PO(OC ₁₄-alkyl)₂ , CO(OC₁₋₅-alkyl), CONH—C ₆ H ₄—(C ₁₋₃-alkyl) or CO—C ₆ H ₄ —R ⁷ , in which R ⁷is ortho-OCOC ₁₋₃-alkyl or meta- or para-CH ₂ N(R ⁸)₂ , where R ⁸ is C₁₋₄-alkyl or 4 -morpholino, or R ⁴ represents meta-S—C ₁₋₃-alkyl,meta-Cl, meta-F, meta-CR ⁹ R ¹⁰ R ¹¹ , ortho-OH, ortho-O—C ₂₋₃-alkyl,para-F or para-CR ⁹ R ¹⁰ R ¹¹ , where R ⁹ , R ¹⁰ and R ¹¹ independentlyrepresent H or F, or R ⁵ represents para-Cl, para-F, para-OH or para-O—C₁₋₃-alkyl, and R ⁴ represents meta-Cl, meta-F, meta-OH or meta-O—C₁₋₃-alkyl, or R ⁴ and R ⁵ together represent 3,4 -OCH═CH— or 3,4-OCH═CHO—, and wherein carbon atoms at positions 1 and 2 are bothasymmetric carbons and the diastereomer has a ( 1R, 2R) or ( 1S, 2S)configuration, or a salt thereof with a physiologically acceptable acid.142. An isolated 1-phenyl- 3 -dimethylaminopropane diastereoisomeraccording to claim 141 , wherein R ⁵ is H, and R ⁴ is meta-OCH ₃ . 143.An isolated 1-phenyl- 3 -dimethylaminopropane diastereoisomer accordingto claim 141 , wherein R ⁵ is H, and R ⁴ is meta-OH.
 144. An isolated1-phenyl- 3 -dimethylaminopropane diastereoisomer according to claim 141, wherein R ² represents CH ₃ ; R ³ is H; and R ⁵ represents H, and R ⁴represents meta-O—C ₁₋₃-alkyl, meta-OH, meta-S—1-3 -alkyl, meta-F,meta-Cl, meta-CH ₃ , meta-CF ₂ H, meta-CF ₃ , or para-CF ₃ , or R ⁵represents para-Cl, or para-F, and R ⁴ represents meta-Cl, or meta-F, orR ⁴ and R ⁵ together represent 3,4 -OCH═CH—.
 145. An isolated 1-phenyl-3 -dimethylaminopropane diastereoisomer according to claim 141 , whereinR ² is CH ₃ , and R ³ is H.
 146. An isolated 1-phenyl- 3-dimethylaminopropane diastereomer according to claim 141 , wherein R ⁹, R ¹⁰ and R ¹¹ represent F.
 147. A pharmaceutically acceptable salt of(−)-( 1R,2R)- 3R-( 3 -dimethylamino- 1 -ethyl- 2 -methylpropyl)-phenol.